The objectives of this research project are broad and are to study metabolism in the ruminant with particular reference to gluconeogenesis and ketogenesis, their interrelationships, mechanisms, and hormonal control. It is also a comparative metabolism project between ruminant and simple-stomached species. Adult ruminants normally absorb only little glucose from their digestive tracts but instead convert dietary carbohydrates to volatile fatty acids (esp. acetate, propionate and butyrate). The ruminant thus must continuously rely upon gluconeogenesis for most of its carbohydrate requirements. Furthermore, much of the butyrate and acetate are converted to ketone bodies by the rumen epithelium before entering the bloodstream. The ruminant digestive tract, unlike that of simple-stomached animals, thus is a major site of ketogenesis. Additionally, hypoglycemia and ketosis frequently occur in late pregnant sheep carrying 2 or more fetuses and in cattle during heavy lactation. In this project, the in situ metabolism of amino acids, and gluconeogenic and ketogenic precursors by the liver and kidneys, as compared with the intact and whole body, is being emphasized. A new method has been developed for measuring portal and liver bloodflow in the unanesthetized and trained sheep and dog. Arteriovenous differences of metabolites are measured as well as the turnover of tritiated and C14-metabolites. This study thus will help elucidate the cause of the insufficient gluconeogenesis during pregnancy ketosis as well as yield information on the mechanism of ketogenesis and metabolism of fatty acids. It is believed that the sheep presents a unique opportunity to study carbohydrate and fat metabolism dyscrasias as applied to both man and animals. In addition, this study will shed light on the basic metabolic adaptations the body undergoes in adapting to fasting, pregnancy, parturition, and lactation, as well as clarifying etiological and pathogenetic features of ketotic and hypoglycemic states.